This invention concerns novel pyrrolobenzodiazepine pyridine carboxamides, which act as follicle-stimulating hormone receptor antagonists, as well as pharmaceutical compositions and methods of treatment utilizing these compounds.
Reproduction in women depends upon the dynamic interaction of several compartments of the female reproductive system. The hypothalamic-pituitary-gonadal axis orchestrates a series of events affecting the ovaries and the uterine-endometrial compartment that leads to the production of mature ova, ovulation, and ultimately, appropriate conditions necessary for fertilization. Specifically, luteinizing hormone-releasing hormone (LHRH), which is released from the hypothalamus, initiates the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. These hormones act directly on the ovary to promote the development of selected follicles by inducing granulosa and theca cell proliferation and differentiation. FSH stimulates aromatization of androgens to estrogens and increases the expression of LH receptors in the theca cells. The follicles, in turn, secrete steroids (estradiol, progesterone) and peptides (inhibin, activin). Estradiol and inhibin levels progressively increase during the follicular phase of the menstrual cycle until ovulation. Inhibin decreases FSH secretion from the pituitary gland, while estradiol acts on the hypothalamus and pituitary to induce the LH surge in mid-cycle, which results in ovulation. Afterwards, the post-ovulation ruptured follicle forms the corpus luteum, which produces progesterone. Ovarian hormones, in turn, regulate the secretion of gonadotropins through a classical long-loop negative feedback mechanism. The elucidation of these control mechanisms has provided opportunities for the development of effective strategies to control fertility, including both enhancement of fertility and contraception. For recent reviews of FSH action see: “FSH Action and Intraovarian Regulation,” B. C. J. M. Fauser, ed., Vol. 6 (London: Parthenon Publishing Group), 1997, and A. J. Hsueh et. al., Rec. Prog. Horm. Res., 45, 209-227, 1989.
Current hormonal contraception methods are steroidal in nature (progestins and estrogens) and modulate long-loop feedback inhibition of gonadotropin secretion, as well as affecting peripheral mechanisms such as sperm migration and fertilization. The development of specific antagonists of the receptor for FSH (FSH-R) would provide an alternative strategy for hormonal contraception. Such antagonists would block FSH-mediated follicular development leading to a blockade of ovulation, thereby producing the desired contraceptive effect. Support for the effectiveness of this strategy is provided by the mechanism that causes resistant ovary syndrome, which results in infertility in women. The infertility experienced by these women is the result of non-functional FSH receptors (K. Aittomaki et al., Cell, 82, 959-968,1995). This approach to contraception may be applicable to men as well, since idiopathic male infertility seems to be related to a reduction in FSH binding sites. In addition, men with selective FSH deficiency are oligo- or azoospermic with normal testosterone levels and present normal virilization (G. Lindstedt et al., Clin. Lab. Med., 36, 664, 1998). Therefore, low molecular weight FSH antagonists may provide a versatile novel method of contraception. Such an antagonist could be expected to interfere with follicle development and thus, ovulation, while maintaining sufficient estrogen production and beneficial effects on bone mass.
FSH actions are mediated by binding of the hormone to a specific transmembrane G protein-coupled receptor that is exclusively expressed in the ovary, thus, leading to activation of the adenyl cyclase system and elevation of intracellular levels of the second messenger cAMP (A. Mukherjee et al., Endocrinology, 137, 3234 1996).
Recently suramin, a sulfonic acid anticancer agent with a wide variety of activities, was shown to inhibit FHS binding to its receptor (R. L. Daugherty et al., J. Urol., 147, 727 (1992). Administration of suramin causes a decrease in testosterone production in rats and humans (R. Danesi et al., J. Clin. Endocrinol. Metab. 81, 2238-2246,1996). Recently, other more selective sulfonic acid-based FSH receptor antagonists were reported by B. J. Arey et al. (The Endocrine Society, 82nd Annual Meeting, Toronto, Canada Jun. 21-24, 2000, and Endocrinology 143 (10), 3822, 2002). An additional class of stilbene (bis)sulfonic acid competitive inhibitors of FSH at its receptor has also been reported by J. Wrobel et al. (Bioorg. Med. Chem. 10, 639-656, 2002).
Thiazolidinone FSH-R agonists and antagonists have been disclosed by R. Scheuerman et al. in WO 02/09705 and WO 02/09706 (2002) and in U.S. Pat. No. 6,426,357 (2002), respectively. Cyclic and acyclic alpha- and beta-aminocarboxamides as FSH-R agonists are disclosed by El Tayer et al. in WO 00/08015 (2000). Substituted aminoalkylamide derivative FSH-R antagonists have been disclosed by Coats et al. in WO 01/47875 (2001). Aryl sulfonic acids and derivatives FSH-R antagonists have been disclosed by Wrobel et al. in U.S. Pat. Nos. 6,200,963 (2001) and 6,355,633 (2002). Tetrahydroquinoline derivatives have been disclosed as FSH-R modulators to control fertility by Van Straten et al. in WO 03/004028 (2003). Bisaryl derivatives with FSH-R modulatory activity have been disclosed by T. Guo et al. in WO 02/070493A1. T. Guo et al. also have reported encoded combinatorial and parallel synthesis approaches to bisaryl FSH-R agonists; see Bioorg. Med. Chem. Lett. 14, 1713-1716, 2004 and 1717-1720, 2004, respectively. Failli et al. in WO 02/083683 (2002) have disclosed a subset of pyrrolobenzodiazepines as tocolytic oxytocin receptor binding antagonists.
It can be seen that there is a great need for FSH receptor binding antagonists that can be used for contraception. This invention is directed to these, as well as other, important ends.